Factors With Adequate Evidence of Increased Risk of Breast Cancer

Sex and age

Based on solid evidence, female sex and increasing age are the major risk factors for the development of breast cancer.

Magnitude of Effect: Women have a lifetime risk of developing breast cancer that is approximately 100 times the risk for men. The short-term risk of breast cancer in a 70-year-old woman is about ten times that of a 30-year-old woman.

Study Design: Many epidemiologic trials.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Major inheritance susceptibility

Based on solid evidence, women who inherit gene mutations associated with breast cancer have an increased risk.

Breast density

Based on solid evidence, women with dense breasts have an increased risk of breast cancer. This is most often an inherent characteristic, to some extent modifiable by reproductive behavior, medications, and alcohol.[1]

Magnitude of Effect: Women with dense breasts have increased risk, proportionate to the degree of density. This increased relative risk (RR) ranges from 1.79 for women with slightly increased density to 4.64 for women with very dense breasts, compared with women who have the lowest breast density.[2]

Study Design: Cohort, case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Modifiable Factors With Adequate Evidence of Increased Risk

Combination hormone therapy

Based on solid evidence, combination hormone therapy (HT) (estrogen-progestin) is associated with an increased risk of developing breast cancer.

Magnitude of Effect: Approximately a 26% increase in incidence of invasive breast cancer; the number needed to produce one excess breast cancer is 237.

Study Design: Randomized controlled trials (RCTs). Furthermore, cohort and ecological studies show that cessation of combination HT is associated with a decrease in rates of breast cancer.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Ionizing radiation

Based on solid evidence, exposure of the breast to ionizing radiation is associated with an increased risk of developing breast cancer, starting 10 years after exposure and persisting lifelong. Risk depends on radiation dose and age at exposure, and is especially high if exposure occurs during puberty, when the breast develops.

Magnitude of Effect: Variable but approximately a sixfold increase overall.

Study Design: Cohort or case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Obesity

Based on solid evidence, obesity is associated with an increased breast cancer risk in postmenopausal women who have not used HT. It is uncertain whether weight reduction decreases the risk of breast cancer in obese women.

Magnitude of Effect: The Women's Health Initiative observational study of 85,917 postmenopausal women found body weight to be associated with breast cancer. Comparing women weighing more than 82.2 kg with those weighing less than 58.7 kg, the RR was 2.85 (95% confidence interval [CI], 1.81–4.49).

Study Design: Case-control and cohort studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Alcohol

Based on solid evidence, alcohol consumption is associated with increased breast cancer risk in a dose-dependent fashion. It is uncertain whether decreasing alcohol intake by heavy drinkers reduces the risk.

Magnitude of Effect: The RR for women consuming approximately four alcoholic drinks per day compared with nondrinkers is 1.32 (95% CI, 1.19–1.45). The RR increases by 7% (95% CI, 5.5%–8.7%) for each drink per day.

Study Design: Case-control and cohort studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Factors With Adequate Evidence of Decreased Risk of Breast Cancer

Early pregnancy

Based on solid evidence, women who have a full-term pregnancy before age 20 years have decreased breast cancer risk.

Magnitude of Effect: 50% decrease in breast cancer, compared with nulliparous women or women who give birth after age 35 years.

Study Design: Case-control and cohort studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Breast-feeding

Based on solid evidence, women who breast-feed have a decreased risk of breast cancer.

Magnitude of Effect: The RR of breast cancer is decreased 4.3% for every 12 months of breast-feeding, in addition to 7% for each birth.[3]

Study Design: Case-control and cohort studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Exercise

Based on solid evidence, exercising strenuously for more than 4 hours per week is associated with reduced breast cancer risk.

Magnitude of Effect: Average RR reduction is 30% to 40%. The effect may be greatest for premenopausal women of normal or low body weight.

Study Design: Prospective observational and case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Estrogen use by women with prior hysterectomy

Benefits

Based on fair evidence, women who have undergone a prior hysterectomy and who are treated with conjugated equine estrogen have a lower incidence of breast cancer. However, epidemiological studies yield conflicting results.

Magnitude of effect: After 6.8 years, incidence was 23% lower in women treated with estrogen in an RCT (0.27% per year, with a median of 5.9 years of use, compared with 0.35% per year among those taking a placebo), but was 30% higher in women treated with estrogen in an observational study. The difference in these results may be explained by different screening behavior by the women in both studies.

Study Design: One RCT, observational studies.

Internal Validity: Fair.

Consistency: Poor.

External Validity: Poor.

Harms

Based on solid evidence, women who have undergone hysterectomy and who are taking postmenopausal estrogen have an increased risk of stroke and total cardiovascular disease.

Magnitude of Effect: There is a 39% increase in the incidence of stroke (RR, 1.39; 95% CI, 1.1–1.77) and a 12% increase in cardiovascular disease (RR, 1.12; 95% CI, 1.01–1.24).

Study Design: RCTs, observational studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Poor.

Interventions With Adequate Evidence of Decreased Risk of Breast Cancer

Selective estrogen receptor modulators (SERMs)

Benefits

Based on solid evidence, tamoxifen and raloxifene reduce the incidence of breast cancer in postmenopausal women, and tamoxifen reduces the risk of breast cancer in high-risk premenopausal women. The effects observed for tamoxifen and raloxifene show persistence several years after active treatment is discontinued, with longer duration of effect noted for tamoxifen than for raloxifene.[4]

All fractures were reduced by SERMs, primarily noted with raloxifene but not with tamoxifen. Reductions in vertebral fractures (34% reduction) and small reductions in nonvertebral fractures (7%) were noted.[4]

Magnitude of Effect: Tamoxifen reduced breast cancer by about 50%. Treatment with raloxifene has a similar effect on reduction of invasive breast cancer but appears to be less effective for the prevention of noninvasive tumors. A meta-analysis showed an overall 38% risk reduction for SERMs in breast cancer incidence. With 5 years of treatment, 42 women would need to be treated to prevent one breast cancer in the first 10 years of follow-up.[4]

Study Design: RCTs.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Harms

Based on solid evidence, tamoxifen treatment increases the risk of endometrial cancer, which was apparent in the first 5 years of follow-up but not beyond; thrombotic vascular events (i.e., pulmonary embolism, stroke, and deep venous thrombosis); and cataracts. Many of these risks are reduced after active treatment with tamoxifen is discontinued. Based on solid evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.

Aromatase inhibitors or inactivators

Benefits

Based on solid evidence, aromatase inhibitors or inactivators (AIs) reduce the incidence of new breast cancers in postmenopausal women who have an increased risk.

Magnitude of Effect: After a median follow-up of 35 months, women aged 35 years and older who had at least one risk factor (age >60 years, a Gail 5-year risk >1.66%, or ductal carcinoma in situ with mastectomy) and who took 25 mg of exemestane daily had a decreased risk of invasive breast cancer (HR, 0.35; 95% CI, 0.18–0.70). The absolute risk reduction was 21 cancers avoided out of 2,280 participants over 35 months. The number needed to treat was about 100.[5]

Study Design: One RCT.

Internal Validity: Good.

Consistency: One study in women with no history of breast cancer but consistent with RCTs in women with history of breast cancer.

External Validity: Good for women who meet inclusion criteria.

Harms

Based on fair evidence from a single RCT of 4,560 women over 35 months, exemestane is associated with hot flashes and fatigue but not with fractures, osteoporosis, or cardiovascular events, compared with placebo.[5]

Magnitude of Effect: The absolute increase in hot flashes was 8% and the absolute increase in fatigue was 2%.

Study Design: One RCT.

Internal Validity: Good.

Consistency: Good.

External Validity: Good for women who meet inclusion criteria.

Prophylactic mastectomy

Benefits

Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history, and most women experience relief from anxiety about breast cancer risk. There are no studies examining breast cancer outcomes in women who undergo contralateral prophylactic mastectomy after surgery for ipsilateral breast cancer.

Magnitude of Effect: Breast cancer risk after bilateral prophylactic mastectomy in women at high risk is reduced as much as 90%, but published study designs may have produced an overestimate.